Conformational control of cofactors in nature – the influence of protein-induced macrocycle distortion on the biological function of tetrapyrroles

Abstract

Tetrapyrrole-containing proteins are one of the most fundamental classes of enzymes in nature and it remains an open question to give a chemical rationale for the multitude of biological reactions that can be catalyzed by these pigmentprotein complexes. There are many fundamental processes where the same (i.e., chemically identical) porphyrin cofactor is involved in chemically quite distinct reactions. For example, heme is the active cofactor for oxygen transport and storage (hemoglobin, myoglobin) and for the incorporation of molecular oxygen in organic substrates (cytochrome P 450 ). It is involved in the terminal oxidation (cytochrome c oxidase) and the metabolism of H 2 O 2 (catalases and peroxidases) and catalyzes various electron transfer reactions in cytochromes. Likewise, in photosynthesis the same chlorophyll cofactor may function as a reaction center pigment (charge separation) or as an accessory pigment (exciton transfer) in light harvesting complexes (e.g., chlorophyll a). Whilst differences in the apoprotein sequences alone cannot explain the often drastic differences in physicochemical properties encountered for the same cofactor in diverse protein complexes, a critical factor for all biological functions must be the close structural interplay between bound cofactors and the respective apoprotein in addition to factors such as hydrogen bonding or electronic effects. Here, we explore how nature can use the same chemical molecule as a cofactor for chemically distinct reactions using the concept of conformational flexibility of tetrapyrroles. The multifaceted roles of tetrapyrroles are discussed in the context of the current knowledge on distorted porphyrins. Contemporary analytical methods now allow a more quantitative look at cofactors in protein complexes and the development of the field is illustrated by case studies on hemeproteins and photosynthetic complexes. Specific tetrapyrrole conformations are now used to prepare bioengineered designer proteins with specific catalytic or photochemical properties.

Macrophages and Iron Metabolism

“…Depending upon the chemical reaction, iron and the surrounding porphyrin macrocycle of heme endow hemoproteins with the capacity to exchange electrons with other molecules (Kleingardner and Bren, 2015; Senge et al, 2015). While electron transfer reactions are also the hallmark of another class of iron-containing prosthetic groups, termed iron-sulfur clusters, we will specifically focus this review on heme.…”

“…Iron exchanges electrons primarily with divalent gaseous molecules such as O 2 , nitric oxide (NO•) or carbon monoxide (CO) (Kleingardner and Bren, 2015; Senge et al, 2015). As gaseous molecules became, through evolution, embedded in vital biological functions, most life forms evolved to generate them endogenously, as exemplified for O 2 in plants and for NO• and CO in most other life forms.…”

Porphyrins as Catalysts in Scalable Organic Reactions

“…A suitable example that can be given is the heme group which contains an iron-porphyrin complex which coordinates oxygen and carbon dioxide for cellular carriage [10], responsible for cellular respiration, and contributing to the catalytic activities of many enzymes as cofactors [11]. This is one of the reasons why porphyrin-derived pigments are called "the Pigments of Life" (Figures 1 and 2) [12,13].…”

A Two-Pronged Attack on DNA: Targeting Guanine Quadruplexes with Nonplanar Porphyrins and DNA-Binding Small Molecules

“…Classic non-planar porphyrins are N-substituted derivatives, wherein core substitution results in macrocycle distortion. Historically, these were developed as inhibitors of ferrochelatase and now are under scrutiny with regard to their DNA interactions [18]. The free-base (core neutral) 21-methyl mesoporphyrin has excellent GQ specificity but relatively poor GQ affinity due to the two propionate side chains [19].…”

“…As outlined, the semi-planar arrangement of the aromatic rings in N-substituted porphyrins provides the potential for specific binding to GQs via stacking on the G-tetrad and locking into the central space. In addition, porphyrins are fluorescent (i.e., suitable for diagnostics) and also can produce reactive oxygen species, thus photochemically inducing strand breaks (although nonplanar porphyrins have lower triplet quantum yields and thus require molecular engineering [18]). Therefore, they offer potential as theranostic agents for nucleic acid targeting.…”